Genetic aberrations that render cells incapable of executing DNA darnage-induced apoptosis, such as loss of p53 or overexpression of Bcl-2, underlie the observed resistance of lymphoid cancers to gamma radiation and chemotherapeutic agents. An alternative mechanism of triggering cell death involves antibody- or ligand-mediated engagement of the CD20 antigen or death receptors for TRAIL (tumor necrosis factor-related apoptosis-inducing ligand)/Apo2L. Our preliminary studies indicate that death receptors and DNA damage induce independent, yet synergistic, signaling pathways that converge at the level of formation of the caspase-9/Apaf- I /Cytochrome c complex. Although this offers a potential mechanism of eliminating p53-deficient or Bcl- 2-overexpressing lymphomas, our studies indicate that death receptor-transduced signals are counteracted by NF-kB, a family of transcription factors that plays an important role in determining lymphocyte survival during immune and stress responses. The constitutive activation of NF-kB by diverse signals such as co stimulatory interactions, viral proteins, or genetic aberrations may protect B cell tumors from death receptor-induced apoptosis. However, our preliminary studies have uncovered two potential strategies for sensitizing tumor cells to death receptor-induced apoptosis. One approach capitalizes on the striking synergy between the cytotoxic effects of the death-receptor and DNA damage-induced signaling pathways. The other approach involves ligation of death receptors in conjunction with agents that inhibit NF-kB. The overall objective of this proposal is to design, develop, and test therapeutic strategies that employ such synergistic combinations to eliminate B-cell malignancies that resist conventional chemotherapeutic agents. The Specific Aims are: 1. Examine whether the combination of TRAIL/Apo2L with targeted delivery of ionizing radiation via radiolabeled anti-CD20 antibodies can eliminate B-cell malignancies without incurring prohibitive toxicity. 2. Examine whether inhibition of NF-kB with agents that target the IkB kinase complex can augment the efficacy of anti-CD20 antibodies in the treatment of B-cell lymphomas. The safety and efficacy of these combination regimens will be investigated in Phase 1/11 clinical trials in patients with chemotherapy-refractory B-cell malignancies. Such antibody- and ligand-based combinatoriao therapy may provide an effective and physiologic approach for inducing tumor cell death that is not complicated by the immediate and long-term toxicities of high dose therapy requiring stem cell transplantation.